Alcohol and other drug use are common in adolescence. Our prior studies found that adolescents with alcohol use disorders (AUD), and even binge drinking in the absence of a diagnosis, show abnormalities on indices of brain functioning, including neuropsychological test performance; hippocampal, prefrontal, and cerebellar volumes; white matter microstructural integrity; and functional magnetic resonance imaging (FMRI) response to cognitive and alcohol cue tasks. However, some of these indices are related to risk factors for adolescent alcohol involvement, such as family history of AUD. Thus, it is unclear if abnormalities observed in adolescent heavy drinkers are caused by alcohol exposure, or predated the onset of heavy drinking. Description: This renewal project will follow 296 youth previously characterized in R01 AA13419 prior to the onset of substance use. At baseline, these youth were 12-14 year-olds free from any psychiatric disorder with, on average, one alcohol use experience, and nearly half at risk for AUD based on family history. Baseline assessments, now complete, included neuropsychological testing and brain imaging with high resolution MRI, FMRI acquisition during working memory and alcohol cue presentation tasks, and diffusion tensor imaging (DTI). In this competing renewal, we will continue to follow these adolescents with quarterly interviews on substance use and general functioning. Each subject who initiates heavy drinking (defined as at least monthly binge drinking episodes), as well as a non-user matched for age, gender, and family history, will be invited back to repeat the protocol 3 times during this 5-year period (independent of whether they remain heavy drinkers or transition out during the duration of the project). As of Year 09, 29% (n=86) have initiated heavy drinking (most typically at age 17), and 61% (n=181) have remained non-drinkers/users (28 fall into neither group). Aims: The goal of this project now is to ascertain if indices of brain functioning (i.e., neuropsychological testing; hippocampal, prefrontal cortex, and cerebellar volumes; white matter microstructural integrity in frontoparietal and fronto-cerebellar tracks, and FMRI response to working memory in frontal and parietal regions and to alcohol cues in reward networks changes after the onset of heavy drinking to a different degree than observed in typically developing adolescents of the same age who do not use substances. We hypothesize that initiation of heavy drinking during adolescence will be associated with alternations in brain structure and function, and that gender will moderate this relationship. Other substance use (marijuana and nicotine) and other risk factors for AUD (externalizing behaviors, level of response to alcohol, and alcohol expectancies) will be evaluated as potential contributors to change in brain functioning. Based on our previous studies, we further hypothesize that baseline brain response patterns will significantly predict substance use involvement and outcomes. Pilot analyses will begin to look at normalization of these neural abnormalities, as some young adults transition out of heavy drinking.